Optically active 5H-pyrrolo[3,4-b] pyrazine derivative, its preparation and pharmaceutical compositions containing same

ABSTRACT

Dextrorotatory isomer of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-l-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, its preparation and pharmaceutical compositions containing it which are usable as tranquillisers and hypnotics.

In French Patent FR 72/00,505, published under number 2,166,314, adescription was given, in particular, of6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine,also known by the name of zopiclone, which is a noteworthy hypnoticproduct.

As a result of the presence of an asymmetric carbon atom at the5-position of the 5H-pyrrolo[3,4-b]-pyrazine ring-system, zopiclone mustbe considered, in racemic form, to consist of a strictly equimolecularmixture of the laevorotatory and dextrorotatory forms.

It has now been found, and this forms the subject of the presentinvention, that the dextrorotatory isomer of zopiclone possessesproperties which are not obvious in the light of those of racemiczopiclone.

The subject of the present invention is hence the dextrorotatory isomerof zopiclone, its preparation and pharmaceutical compositions containingit. In a racemic product, it is known that, often, one of the twoenantiomers is active and that an enhancement of the toxicity may belinked to this activity, the other enantiomer being both markedly lessactive or inactive and less toxic. For such products, the gain inactivity does not compensate for the drawbacks due to an enhancedtoxicity.

In the case of zopiclone, it was found, surprisingly and unexpectedly,not only that the dextrorotatory isomer is approximately twice as activeas the racemate while having a lower toxicity than that of the racemate,but that the laevorotatory isomer is both almost inactive and more toxicthan the racemate.

For example, when administered orally to mice, zopiclone possesses atoxicity (LD₅0) in the region of 850 mg/kg, whereas the dextrorotatoryisomer has a toxicity in the region of 1.5 g/kg and the laevorotatoryisomer possesses an LD₅0 of between 300 and 900 mg/kg.

In animals, the dextrorotatory isomer of zopiclone displays hypnotic,sedative, anxiolytic, muscle-relaxant and anticonvulsant properties.

From the standpoint of the potency of action in the main testsdemonstrating the tranquillising and hypnotic activity of zopiclone,such as the test of affinity for central benzodiazepine receptor sitesaccording to the technique of J. C. Blanchard and L. Julou, J. ofNeurochemistry, 40, 601 (1983) based on the work of Squires andBraestrup, Nature, 266, 732-734 (1977), or the test of antagonistactivity with respect to pentetrazol-induced convulsions according tothe technique of Everett and Richards, J. Pharmacol., 81, 402 (1944), orin the writhing reflex test in mice according to the technique of2binden and Randall, Advances in Pharmacology 5, 213-291 (1967), thedextrorotatory isomer is approximately twice as active whereas thelaevorotatory isomer is almost inactive.

According to the invention, the dextrorotatory isomer of zopiclone maybe prepared from the corresponding racemate according to the usualmethods, such as chiral-phase chromatography, resolution of an opticallyactive salt, stereoselective enzymatic catalysis by means of anappropriate microorganism, or asymmetric synthesis.

More especially, the dextrorotatory isomer of zopiclone may be obtainedby resolution of zopiclone by means of an optically active acid, workingin an appropriate organic solvent.

As an optically active acid which is especially suitable,D(+)-O,O′-dibenzoyltartaric acid may be mentioned.

Generally, the reaction is performed in an organic solvent chosen fromhalogenated aliphatic hydrocarbons such as dichioromethane and nitrilessuch as acetonitrile, taken alone or mixed.

By working in this manner, the salt of the dextrorotatory isomerprecipitates and the laevorotatory isomer is extracted from the motherliquors of crystallisation.

The dextrorotatory isomer of zopiclone is displaced from its salt bymeans of a base such as sodium hydroxide.

The dextrorotatory isomer of zopiclone is useful in humans for thetreatment of states due to a dysfunction of the central nervous system.

The dextrorotatory isomer of zopiclone is, e.g., useful as ahypnosedative, tranquilliser, muscle relaxant and anticonvulsant.

However, the dextrorotatory isomer of zopiclone is more especiallyuseful in man as a hypnotic.

Since it acts on the various parameters of sleep, the dextrorotatoryisomer of zopiclone increases sleeptime and improves sleep quality, anddecreases the number of episodes of waking at night and of early morningawakening.

The present invention relates to pharmaceutical compositions containingthe dextrorotatory isomer of zopiclone or one of its pharmaceuticallyacceptable salts, in the pure state or in the presence of a diluent or acoating. These compositions may be employed orally, rectally orparenterally.

As pharmaceutically acceptable salts, salts of inorganic acids (such ashydrochlorides, sulphates, nitrates, phosphates) or organic acids (suchas the acetates, propionates, succinates, benzoates, fumarates,tartrates, theophyllineacetates, salicylates, phenolphthalinates,methylenebis(β-hydroxynaphthoates), or of substitution derivatives ofthese acids, may be mentioned.

As solid compositions for oral administration, tablets, pills, powdersor granules may be used. In these compositions, the active productaccording to the invention is mixed with one or more inert diluents suchas sucrose, lactose or starch. These compositions can also comprisesubstances other than diluents, e.g. a lubricant such as magnesiumstearate.

As liquid compositions for oral administration, solutions, suspensions,syrups, elixirs and pharmaceutically acceptable emulsions, containinginert diluents such as water or liquid paraffin, may be used. Thesecompositions can also comprise substances other than diluents, e.g.wetting, sweetening or flavouring products.

The compositions for parenteral administration can be suspensions,emulsions or aqueous or non-aqueous, sterile solutions. As a solvent orvehicle, propylene glycol, polyethylene glycol, vegetable oils,especially olive oil, and injectable organic esters, e.g. ethyl oleate,may be employed. These compositions can contain adjuvants, especiallywetting, emulsifying and dispersing agents. The sterilisation may becarried out in several ways, e.g. using a bacteriological filter, byincorporating sterilising agents in the composition, by irradiation orby heating. They may be prepared in the form of sterile compositionswhich can be dissolved at the time of use in sterile water or any othersterile injectable medium.

The compositions for rectal administration are suppositories which cancontain, apart from the active product, excipients such as cocoa butter.

In human therapy, the doses depend on the effect sought and thetreatment period; taken orally, they are generally between 2.5 and 15 mgper day for an adult.

The examples which follow, given without implied limitation, illustratethe present invention.

EXAMPLE1

A solution of zopiclone (23.28 g; 0.06 mol) in dichloromethane (300 cc)is added to a solution of D(+)-O,O′-dibenzoyltartaric acid in the formof a monohydrate (22.56 g; 0.06 mol) in dichloromethane (300 cc). Thereaction mixture is concentrated to dryness under reduced pressure. Thecrude salt obtained is recrystallised in acetonitrile (2000 cc) to give,in a 46% yield, a crystallised product (21.3 g), m.p. 160-165° C. (withdecomposition), the optical rotation of which is [α]_(D) ²⁰=83° (c=0.5;acetone).

The product obtained is dissolved in dichloromethane (180 cc) underreflux. Acetonitrile (200 cc) is added and the mixture is left standingfor 1 our at a temperature of 5° C. The crystallised product obtained isrecrystallised again under the same conditions. A crystallised salt(16.5 g), m.p. 160-165° C. (with decomposition), the optical rotation ofwhich is [α]_(D) ²⁰=102° (c=0.5; acetone), is thereby obtained in a 36%yield.

The salt thereby obtained is dissolved in water (125 cc) in the presenceof dichloromethane (125 cc). The mixture is alkalinised to pH 11 byslowly -adding 2N aqueous sodium hydroxide solution. After settling hastaken place, the aqueous phase is separated and extracted twice withdichloromethane. The combined organic phases are washed with water andthen dried over magnesium sulphate. After filtration, evaporation of thesolvent and recrystallisation of the product obtained in acetonitrile(80 cc), the dextrorotatory isomer (5.4 g) of zopiclone, m.p. 206.5° C.,the optical rotation of which is [α]_(D) ²⁰=135°±3° (c=1.0; acetone), isobtained in a 23% yield.

The mother liquors of crystallisation of the salt of zopiclone withD(+)-O,O′-dibenzoyltartaric acid are concentrated to dryness underreduced pressure to give a salt (22.05 g) the optical rotation of whichis [α]_(D) ²⁰=−21° (c=0.2; acetone).

The salt thereby obtained is dissolved in water (125 cc) in the presenceof dichloromethane (125 cc). The mixture is alkalinised to pH 11 byslowly adding 2N aqueous sodium hydroxide solution. After settling hastaken place, the aqueous phase is separated and extracted twice withdichloromethane. The combined organic phases are washed with water andthen dried over magnesium sulphate. After filtration and evaporation ofthe solvent, the crystallised solid obtained (8.45 g) is recrystallisedin acetonitrile (successively 100, 50 and 45 cc). The laevorotatoryisomer (3.13 g) of zopiclone, m.p. 206.9° C., the optical rotation ofwhich is [α]_(D) ²⁰=±133° (c=1.0; acetone), is thereby obtained in a13.9% yield.

EXAMPLE 2

Tablets containing 3 mg of active product and having the followingcomposition are prepared according to the usual technique:dextrorotatory isomer of zopiclone 0.003 g starch 0.100 g precipitatedsilica 0.035 g magnesium stearate 0.005 g

1-4. (Cancelled)
 5. A method of making a dextrorotatory isomer ofzopiclone,6-)5-chloro-2-pyridyl)-5-[4-methyl-1-piperazinyl)-carbonyloxy]-7-oxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine,and pharmaceutically acceptable salts thereof, comprising the steps of:a) forming a first reaction mixture by mixing a solution of an opticallyactive acid in dichloromethane to a solution of zopiclone in a firstorganic solvent; b) concentrating the reaction mixture to dryness underreduced pressure to form a dry salt; c) recrystallizing the salt in asecond organic solvent to form a first crystallized product; d)dissolving the crystallized product in a third organic solvent withreflux; e) adding a fourth organic solvent to form a second reactionmixture; f) maintaining the second reaction mixture to form a secondcrystallized product and recrystallizing the second crystallized productto obtain a crystallized salt; g) dissolving the crystallized salt inwater in the presence of a fifth organic solvent to form a thirdreaction mixture; h) alkalizing the third reaction mixture to pH 11,collecting a first organic phase, extracting a remaining aqueous phaseat least once with a sixth organic solvent to obtain a second organicphase, collecting the second organic phase, and recombining the firstand second organic phases; i) washing the recombined organic phases inwater, then drying over magnesium sulfate, then filtering; j)evaporating the solvent and recrystallizing the resulting product in aseventh organic solvent to obtain a dextrorotatory zopiclone isomer. 6.The method according to claim 5, wherein the first crystallized producthas a melting temperature of 160-165° C. and a rotatory power of [β]²⁰_(D)=83° (c=0.5; acitone.)
 7. The method according to claim 5, whereinthe second reaction mixture is maintained for 1 hour at 5° C.
 8. Themethod according to claim 5, wherein the crystallized salt has a meltingtemperature of 160-165° C. and a rotory power of [β]²⁰ _(D)=102° (c=0.5;acitone).
 9. The method according to claim 5, wherein the alkalizing ofthe third reaction mixture is achieved by the slow addition of a basicaqueous solution.
 10. The method according to claim 5, wherein thedextrorotatory zopiclone isomer has a melting temperature of 206.5° C.and [β]²⁰ _(D)=135°±3° (c=1.0; acetone).
 11. The method according toclaim 5, wherein optically active acid is D(+)-O,O′-dibenzoyltartaricacid.
 12. The method according to claim 5, wherein each of the first,third, fifth, and sixth organic solvents is independently selected fromthe group consisting of halogenated aliphatic hydrocarbons.
 13. Themethod according to claim 12, wherein each halogenated aliphatichydrocarbon is independently selected from the group consisting ofdichloromethane, a nitrile, and combinations thereof.
 14. The methodaccording to claim 13, wherein the nitrile is acetonitrile.
 15. Themethod according to claim 5, wherein the pharmaceutically acceptablesalts are salts of mineral acids, or substitution derivatives thereof,selected from the group consisting of hydrochlorides, sulfates,nitrates, and phosphates.
 16. The method according to claim 5, whereinthe pharmaceutically acceptable salts are salts of organic acids, orsubstitution derivatives thereof, selected from the group consisting ofacetates, propionates, succinates, benzoates, fumarates, tartrates,theophyllineacetates, salicylates, phenolphthalinates, andmethylene-bis-β-hydroxynaphthoates.